Abstract
The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.
Highlights
The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies
To assess the effects of 4-MU and ursolic acid (UA) on melanoma cell metabolism, we evaluated oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XFe96 Analyzer
One of the positive hits identified in this screen was 4-MU, a derivative of coumarin that has been approved in Europe and Asia for the treatment of biliary spasm under the name hymecromone. 4-MU inhibits the synthesis of hyaluronic acid (HA) and has demonstrated anti-tumor activity in several cancer cell lines in vitro, with a potency similar to that observed here[36,37,38]
Summary
The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma. Given the frequent development of resistance to targeted melanoma monotherapies, it is important to identify drug combinations that can lead to durable patient responses One such strategy is to co-target components of the MAPK pathway, such as BRAF and MEK, which has proven to be effective in the treatment of metastatic melanoma[10,11,12]. For some of these compounds, synthetic derivatives have been developed to improve potency and specificity[20,26]
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